PT  - JOURNAL ARTICLE
AU  - Meenakshi Chakraborty
AU  - Sofia Hu
AU  - Marco Del Giudice
AU  - Andrea De Martino
AU  - Carla Bosia
AU  - Phillip A. Sharp
AU  - Salil Garg
TI  - Networks of enhancers and microRNAs drive variation in cell states
AID  - 10.1101/668145
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 668145
4099  - http://biorxiv.org/content/early/2019/06/12/668145.short
4100  - http://biorxiv.org/content/early/2019/06/12/668145.full
AB  - Cell-to-cell variation in gene expression is a common feature of developmental processes. Yet, it remains unclear whether molecular mediators can generate variation and how this process is coordinated across loci to allow the emergence of new cell states. Using embryonic stem cells (ESCs) as a model of development, we found interconverting cell states that resemble developmental expression programs and vary in activity at specific enhancers, such as those regulating pluripotency genes Nanog and Sox2 but not Pou5f1 (Oct4). Variable enhancers drive expression of variable genes, including those encoding microRNAs (miRNAs). Notably, variable miRNAs increase cell-to-cell variation by acting on neighborhoods of pluripotency genes. The encoded, variable pluripotency factors bind variable enhancers, forming a feedback loop that amplifies variation and allows the emergence of new cell states. These findings suggest gene regulatory networks composed of enhancers, protein-coding genes, and miRNAs harness inherent variation into developmental outcomes.